Immunotherapy Bridge 2021 and Melanoma Bridge 2021: meeting abstracts

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controlled, sustained, and preferential IL-2 pathway signal. BEMPEG (monotherapy and in combination with NIVO) increases proliferation and infiltration of CD8 + cytotoxic T cells and natural killer cells with limited expansion of unwanted regulatory T cells in the tumor microenvironment [2][3][4]. Additionally, BEMPEG upregulates programmed cell death protein 1 (PD-1) on T cells as well as expression of PD-ligand 1 (PD-L1) in tumor tissue. This mechanism of action of BEMPEG supports its evaluation in combination with an ICI. In a phase 2 cohort of the PIVOT-02 trial (NCT02983045), BEMPEG plus NIVO was well tolerated and produced deep and durable responses in previously untreated patients with metastatic melanoma (N = 41) [4]. This phase 3, randomized, open-label study (PIVOT-12; NCT04410445) is exploring BEM-PEG plus NIVO as adjuvant treatment for patients with completely resected cutaneous melanoma at high risk for recurrence. Patients and methods: Eligible patients are age ≥ 12 years with histologically confirmed stage IIIA (lymph node metastases > 1 mm), IIIB/C/D, or IV (M1a/b/c/d) cutaneous melanoma (AJCC, 8th edition) that has been completely surgically resected (no evidence of residual disease) within 12 weeks prior to randomization (Fig. 1). Other eligibility criteria include tumor tissue provided for central analysis of PD-L1 expression (Dako PD-L1 IHC 28-8 pharmDx), no prior therapy for melanoma (except surgery and/or adjuvant radiation for CNS lesions), and no prior immunotherapy. Eligible patients will be randomized 1:1 to Arm A (BEMPEG 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W) or Arm B (NIVO 480 mg IV Q4W). The primary objective is to compare the efficacy, as measured by RFS by BICR, of BEMPEG plus NIVO vs NIVO alone. Secondary endpoints include overall survival, distant metastasis-free survival (by BICR and investigator assessment in patients with stage III disease), safety and tolerability, and patient-reported outcomes. This trial is currently recruiting globally (Australia, Europe, New Zealand, and the United States), with a planned total enrollment of 950 patients.

Journal of Translational Medicine
Background: The efficacy of BRAF + MEK inhibitors for melanoma patients harboring BRAF mutations is limited by drug resistance; from here, the need to identify additional therapeutic approaches. Towards this goal, our group has demonstrated that microRNAs act as facilitators or antagonists of this phenomenon. This has both diagnostic and therapeutic implications; here, we have addressed the latters. Our nanotechnology approach, aimed to overcome the biopharmaceutical issues of the use of miRNAs in therapy, i.e. their rapid degradation in bloodstream and the poor intracellular uptake, has been to use lipid nanoparticles (LNPs) carrying the oncosuppressive miR-204-5p and miR-199b-5p for in vitro and in vivo efficacy studies. Material and Methods: BRAF-mutant melanoma cell lines, namely M14 and A375, and their MAPKi-resistant counterparts have been subjected to: a) RNA-seq experiments and b) treatments using LNPs carrying miR-204-5p and miR-199b-5p. Gene Set Enrichment Analysis (GSEA) has been interrogated to identify the molecular pathways/ genes affected by these miRNAs. Elisa assays have been used to assess the levels of cytokines in media coming from LNP-treated or not MAPKi-resistant cells. CD1 nude mice have been injected with M14 and A375 cells and treated with BRAFi + MEKi in the presence or not of LNPs to assess the efficacy of these combinatorial regimens. Results: Starting from RNA-seq of two BRAF-mutant melanoma models rendered resistant to MAPKi in vitro implemented with GSEA bioinformatics analyses, we identified the molecular pathways/genes affected by oncosuppressive miR-204-5p and miR-199b-5p. They mostly rewire the alteration of cytokines and chemokines responsible for EMT, hypoxia and extracellular matrix degradation. In particular, we have demonstrated that VEGFa, TGFb1, CCL5 and CXCL2 are aberrantly released by drug resistant melanoma cells and their levels are restored upon LNP stimulation in vitro. According to the capability of these soluble factors to reprogram microenvironment responsible for tumor progression and therapy failure, we observed that cell media coming from resistant cells is able to trigger the migration and polarization of macrophages toward a pro-tumoral M2-type phenotype. Again, this phenomenon was strongly impaired by LNP treatments. Finally, using mouse models xenografted with M14 and A375 cells, we have demonstrated that LNPs carrying miR-204-5p and miR-199b-5p are able to reduce tumor growth as single agents and better when combined with MAPKi. Conclusions: To our knowledge this is the first study combining LNPs carrying oncosuppressive miRNAs with target therapy in cancer and pave the way to propose them as a novel therapeutic option for BRAFmutant melanoma patients.
Background: Despite recent melanoma treatment advances, mucosal melanoma remains particularly difficult to treat with response rates to frontline checkpoint inhibitor (CPI) monotherapy and progressionfree survival times of < 10% and ~ 3 months, which are approximately half the figures for cutaneous melanoma. Responses are even worse in CPI-experienced patients. Nemvaleukin alfa (nemvaleukin) is a novel engineered cytokine that selectively binds to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8 + T and NK cells, with minimal expansion of T regs . Nemvaleukin is being evaluated for treatment of advanced solid tumors, including melanoma, in ARTISTRY-1 (NCT02799095). Materials and methods: Eligible patients with advanced melanoma (cutaneous, mucosal, uveal, acral) previously treated with a CPI were enrolled into a melanoma-specific cohort of ARTISTRY-1 Part B. Intravenous nemvaleukin (6 µg/kg) was administered for 5 days every cycle (14 days, cycle 1; 21 days, cycle 2 +). If patients had disease progression (after ≥ 2 cycles) or stable disease (after ≥ 4 cycles), they could enroll into Part C to receive nemvaleukin and pembrolizumab. Outcomes presented include antitumor activity (RECIST v1.1), pharmacodynamics, and safety as of August 2021. Results: Forty-seven patients, all CPI-experienced, with advanced melanoma received nemvaleukin in Part B (≤ 28 cycles). Median age was 66 years (range, 37-80); median prior lines of therapy was 3 (range, 1-6). Of 46 evaluable patients, 33 had stable disease. Partial responses were observed in 4 patients, 2 (1 confirmed) of 6 with mucosal melanoma and 2 (1 confirmed) of 40 with cutaneous melanoma. Nemvaleukin induced robust expansion of CD8 + T and NK cells, with minimal effect on T regs . Treatment-emergent adverse events (AEs) (> 45%), regardless of causality, were pyrexia (66.0%) and nausea (51.1%). Grade ≥ 3 nemvaleukin-related AEs (> 10%) were neutropenia (40.4%) and decreased neutrophil count (17.0%). There were no deaths due to AEs. Three patients had AEs resulting in discontinuation: intestinal obstruction and failure to thrive (both unrelated to treatment) and confusion (related to treatment). Thirteen patients continue monotherapy (Part B) and 22 rolled over to Part C (combination therapy). Of 12 evaluable patients receiving combination therapy, 6 had stable disease, 3 of whom had progression on monotherapy. No additional safety signals were observed. Conclusions: Nemvaleukin was well tolerated and provided evidence of antitumor activity in CPI-experienced patients with advanced melanoma. The US FDA granted nemvaleukin Orphan Drug and Fast Track designations for mucosal melanoma. A phase 2 study (ARTISTRY-6) Background: Metastatic uveal melanoma (mUM) has a poor prognosis with a 1-yr OS rate of 52%. No systemic treatment has proven an OS benefit in randomized trials. Tebentafusp (tebe), a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100 + cells, has shown promising activity in previously treated mUM pts. Here, we report the primary analysis of overall survival (OS) in the intention-to-treat population (ITT) of a Ph3 trial of tebe vs. investigator's choice (IC) as first line (1L) therapy in pts with mUM [NCT03070392]. Material and methods: In this randomized, open-label, Ph3 trial, 1L HLA-A*02:01 + pts with mUM were randomized 2:1 to receive tebe or IC of pembrolizumab, ipilimumab or dacarbazine, stratified by LDH. The primary endpoint was OS, defined as the time from randomization to death from any cause. Dual primary objectives were to evaluate 1) OS in the ITT population by comparing all tebe-randomized pts to all IC-randomized pts; and 2) OS in tebentafusp-treated patients with rash during week 1 versus all IC-treated patients. Secondary endpoints included safety and RECIST-defined overall response rate, progression free survival and disease control rate. Here we present the OS in the ITT population. The study was unblinded by an independent data monitoring committee at the first pre-specified interim analysis. This analysis was conducted on the first interim analysis (data extracted Nov 2020). Results: 378 pts were randomized to tebe (252) or IC, including pembrolizumab (103), ipilimumab (15) or dacarbazine (7). Tebe significantly prolonged OS compared to IC (HR 0.51; 95% CI 0.36-0.71; P < 0.0001) in the ITT population, with estimated 1-yr OS rate of 73.2% (95% CI 66.3-78.9) vs 57.5% (95% CI 47.0-66.6), respectively. Most common TRAEs were skin-related (gp100+ melanocytes) or cytokine-mediated (T cell activation) and included pyrexia, pruritus, and rash. These AEs decreased in frequency and severity after initial 3-4 doses and were generally manageable with standard interventions. In the tebe arm, the rate of treatment discontinuation due to TRAEs was low (<4%), and there were no treatment-related deaths.

Background:
The prevalence of type 2 diabetes mellitus (T2DM) is significantly increased in women with differentiated thyroid cancer (DTC) and influences overall survival. T2DM is characterized by a progressive status of chronic, low-grade inflammation with an altered number and function of immune cells, both innate and acquired immunity [1]. Tumor necrosis factor receptor 2 (TNFR2) expression is linked to tolerogenic immune reactions and cells with suppressor function, including a subset of T-regulatory cells [2]. Ablative radiotherapy dramatically increases T-cell priming in draining lymphoid tissues, leading to reduction/eradication of the primary tumor or distant metastasis in a CD8 + T cell-dependent fashion [3]. We hypothesized that B cells play a key role in controlling the T-cell responses to radioiodine (131I) therapy in patients with DTC and DTC associated with T2DM (DTC + T2DM). Our study aimed to evaluate the effects of 131I on TNFR2 and B cells in DTC and DTC + T2DM patients. Material and Methods: Peripheral blood was collected from 42 female patients with DTC (mean age 44.6 ± 10.7 years) and 16 with DTC + T2DM (mean age 50.1 ± 9.8 years) before and 4 days after the I-131 administration (3.7 GBq). The distribution of circulating lymphocyte subpopulations was measured by flow cytometry and the serum levels of TNFR2 by ELISA. A dose calibrator was used to measure blood activity with a microcurie accuracy. Results: Radioactivity of the blood samples was higher in DTC + T2DM patients than in those without T2DM (P < 0.001). Increased radioactivity of blood collected 4 days after the same dose of 131 I /patient intake indicates a low 131 I uptake in the DTC + T2DM group. In the presence of T2DM, 131 I led to an increase in the serum TNFR2 concentration (P = 0.01), CD19 + B-lymphocytes (P = 0.03), and a reduction in CD8 + T-cells count number (P = 0.02). In contrast, in DTC patients, 131 I therapy resulted in enhanced anti-tumor immunity mediated by CD8 + T-cells (P = 0.04) by inhibiting TNFR2. Conclusions: The therapeutic efficacy of targeted radionuclide therapy with high-dose depends on the presence of CD8 + T cells both before and after 131 I intake. Our results suggest that proliferation of CD8 + T cells after 131 I is reduced in the presence of TNFR2 and CD-19 + B cells in DTC + T2DM. Background: Tebe is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100 + cells. In this Phase (Ph) 3, randomized trial of first line (1L) metastatic uveal melanoma (mUM) [NCT03070392], tebe significantly improved overall survival (OS) vs. investigator's choice (IC) in the intention-to-treat population (ITT). In previous trials, tebe-related skin adverse events (AEs), hypothesized to be on-target, off-tumor activity against gp100-expressing melanocytes, were associated with improved OS. This association was tested prospectively as co-primary endpoint in the Ph3 study. Material and methods: 378 1L HLA-A*02:01 + mUM pts were randomized 2:1 to tebe (n = 252) or IC (n = 126). Co-primary endpoints were 1) OS in all randomized pts (ITT) and 2) OS in teberandomized pts who develop any grade rash in week 1 vs. all receiving IC. Rash was a composite of preferred AE terms. Melanocyte-related AEs (MRAEs) were defined as pigment change AEs in skin or hair. Overall study-wide alpha was controlled at 0.05, with 90% assigned to ITT and 10% to rash. This analysis was conducted on the first interim analysis (Nov-2020). Results: In 245 tebe-treated pts, the most frequent skin-related AEs included rash (at any time) in 201 pts (82%), pruritis in 167 pts (68%), MRAEs in 109 pts (45%) and erythema in 69 pts (28%). While rash, erythema and pruritis mostly occurred in the first 4 weeks, MRAEs occurred after a median of 2.7 mo. Rash occurred in 146 pts (60%) by week 1; 179 pts (73%) by week 2; and 195 pts (80%) by week 3. Tebe pts with week 1 rash had significantly longer OS vs. IC arm, HR 0.35 (95% CI 0.23, 0.53), p < 0.0001. The estimated 1-yr OS rates were 83% vs 58%, respectively. When expanded to include tebe pts with rash through week 3, the 1-yr OS rate of 75% was still numerically Journal of Translational Medicine 2022, 20(Suppl 1):142

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Ready to submit your research Ready to submit your research ? Choose BMC and benefit from: ? Choose BMC and benefit from: Results: As of June 2021, the combination continued to be generally well tolerated with no new safety signals identified. The objective response rate (ORR) in PD1 naïve cutaneous melanoma pts (n = 8) was 62.5% and 31.3% in anti-PD1 failed (n = 16). The ORR in CSCC (n = 15) was 60% including 46.6% durable CRs. ORR in BCC (n = 4), MCC (n = 4) and angiosarcoma (n = 5) were 25%, 75% and 60% respectively. Responses have been observed to be durable and to deepen over time.
Conclusions: RP1 in combination with nivo provides durable antitumor activity in pts with skin cancers, including CSCC, and anti-PD1/ anti-CTLA-4 failed melanoma. Based on this data, the clinical trial has been expanded to include a registration directed cohort of pts who have anti-PD1 failed cutaneous melanoma (125 pts) and pts with anti-PD1 failed non-small cell lung cancer, anti-PD1 failed MSI-H cancers and anti-PD1 failed NMSC. Clinical Trial registration: NCT03767348.